Post-surgical adhesions are a significant cause of post-operative pain and other surgical complications. Oxidative stress and hypoxia play an important role in adhesion formation. Hypoxia triggers a cascade of responses that ultimately lead to adhesion formation. Development of adhesions is a multistep process, comprising a macrophage-driven inflammatory response, formation of a fibrinous exudate, recruitment of fibroblasts that become activated to form myofibroblasts, excess collagen fiber deposition and subsequent vascularization. These processes occur in a low oxygen environment (hypoxia), which critically modulates inflammation and healing. On the molecular level, responses to hypoxia are orchestrated by hypoxia-inducible factors (HIFs), consisting of an oxygen-dependent α- (HIF-1α, HIF-2α) and an oxygen-independent β-subunit. HIF-α-subunits are constitutively expressed and rapidly degraded in normoxia. In hypoxia, however, HIF-1α and HIF-2α are stabilized and form active transcription complexes. The complexes bind to hypoxia response elements (HRE) in the promoter region of numerous downstream target genes, which collectively mount the adaptive response to hypoxia.
Under normoxic conditions, glucose is catabolized intracellularly to form pyruvate, which is further metabolized to produce adenosine triphosphate (ATP) via the citric acid cycle (TCA cycle). Conversely, under hypoxic conditions, the amount of pyruvate entering the TCA cycle is decreased and pyruvate is converted to lactate. Anaerobic glycolysis is activated by hypoxia-inducible factors (HIFs), which shift metabolism towards anaerobic glycolysis by altering glycolytic enzymes. HIFs inhibit pyruvate dehydrogenase, which converts pyruvate into acetyl CoA, and stimulate lactate dehydrogenase (LDH), which converts pyruvate into lactate; thus leading to increased production of lactate. Lactate may be crucial to adhesion formation through stimulation of other factors involved in adhesion formation such as VEGF and collagen.
U.S. Pat. No. 9,011,883 describes methods for treating or reducing adhesions in the peritoneum of a patient comprising administering an effective amount of L-glutamine or a dipeptide comprising alanyl-glutamine during or after a surgical procedure that affects the peritoneum of the patient.
Recently, it was reported that a single intraoperative lavage with a HIF-1α inhibitor (20 mg/kg) reduced adhesion formation in a mouse model [Strowitzki, M. J., et al., Sci Rep, 2017. 7(1): p. 13151]. The results in vivo were confirmed at the cellular level, where hypoxic up-regulation of several biomarkers of inflammation, including HIF-1α and TGF-β, was blunted in normal murine peritoneal fibroblasts in vitro upon treatment with micromolar doses of a HIF-1α inhibitor.
There is a need in the art for compounds and methods for treating and preventing adhesions, and more particularly hypoxia-associated tissue damage.